Previously, by using a semi-homologous system of gnotobiotic newborn pigs and virulent porcine rotavirus (strain SB-1A) and avirulent human rotavirus (strain DS-1) and their reassortants, we demonstrated that: (i) the 3rd (VP3), 4th (VP4), 9th (VP7), or 10th (NS28) porcine rotavirus gene each play an important independent role in virulence of rotavirus infection in piglets, and (ii) all four of the porcine rotavirus virulence-associated genes are required for the induction of diarrhea and the shedding of virus by piglets. These observations suggested a new potential strategy for attenuation of wild-type human rotaviruses of major epidemiologic importance and the subsequent development of a safe and effective vaccine. Based on this strategy efforts were made to generate four human x bovine rotavirus reassortants, each of which has: (i) the VP4-encoding gene from human rotavirus Wa (VP4:1A); (ii) the VP7-encoding gene from human rotavirus D (VP7:1), DS-1 (VP7:2), P (VP7:3), or ST3 (VP7:4); and (iii) the remaining 9 genes including the VP3-encoding gene and NS28-encoding gene from bovine rotavirus UK. In addition, we successfully generated two human x bovine rotavirus reassortants, each of which had the VP4- encoding gene from human rotavirus Wa (VP4:1A) or DS-1 (VP4:1B) and the remaining 10 genes from bovine rotavirus UK.